Lyme disease, due to infection with the spirochete Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. The disease occurs in stages and is largely due to the host immune response to the spirochete as it adapts to persist in the mammalian host. Innate immunity is provides the first line of defense against spirochete invasion and is critical for the induction of protective adaptive immune responses. Members of the Toll-like receptor (TLR) family of pattern recognition molecules allow innate immune cells to recognize and respond to Bb components. Although essential for host defense, innate immunity also gives rise to the immunopathology of Bb-associated disease. This proposal is based on our recent findings that absence of MyD88, an intracellular adaptor molecule required for TLR-induced inflammation, does not eliminate disease in Bb-infected mice, but severely impairs the ability of the host to control infection despite strong humoral immunity. The objectives of this proposal are to 1) determine the mechanisms through which Bb activates innate immune cells in vitro in the absence of MyD88-dependent TLR signaling; 2) define the defect in innate and/or adaptive immune response that leads to uncontrolled pathogen expansion in MyD88-deficient mice; 3) using double knock-out mice, determine the contribution of antibody, Fc receptors and l complement in MyD88-independent disease expression; 4) using RNA interference and conditional mutant mice, define the role of MyD88-dependent TLR responses in the control of Bb in the persistent phase of Bb infection; and 4) using Bb gene arrays, determine gene expression of spirochetes that persist in the antibody-responsive host. The results of these studies will provide new insight into the pathways utilized by innate immunity to recognize and respond to Bb and other extracellular pathogens. Understanding the contribution of these pathways to induction of inflammation may suggest new targets for therapeutic intervention or for enhancing immunity in inflammatory disorders, both infectious and non-infectious in origin. For the field of Lyme disease, defining the key molecules expressed by host-adapted spirochetes will move us one step closer toward understanding how this pathogen persists in an immunologically responsive host.